Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Altered epigenetic modifications lead to cancer evolution and progression. Pastore and colleagues integrated DNA methylation (DNAme), histone modification, and RNA-seq data in 22 primary chronic lymphocytic leukemia (CLL) and 13 healthy donor B lymphocyte samples. CLL differed from normal B cells at 297 differentially regulated super-enhancers (SE) and 41057 differentially methylated regions. CLL-specific SEs were hypomethylated in proximity to BCL2, LEF1, and CTLA4, genes involved in lymphocyte proliferation and differentiation. Further integration of single-cell DNAme data verified the corrupted coherence of epigenetic modifications and decreased mutual information in epigenetic-transcriptional coordination in CLL, suggesting cell-to-cell heterogeneity. Moreover, mutually exclusive activating and repressing histone marks colocalized in corrupted chromatin states, indicating intratumoral heterogeneity. Data mining at corrupted regions revealed dysregulation of transcription by polycomb-mediated repression of MYC targets, indicative of CLL evolution.Expert Commentary: This work offers mechanistic insights into the intratumoral epigenetic variability of CLL and its transcriptional diversity. Such differential epigenetic and transcriptional states may enable activation of alternate gene regulatory programs associated with therapy resistance and lineage plasticity.Pastore A, Gaiti F, Lu SX, Brand RM, Kulm S, Chaligne R, et al. Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL. Nat Commun 2019;10:1874. doi: 10.1038/s41467-019-09645-5.Investigating the chemokine receptor CXCR3 and its ligands in the context of anti-PD1 treatment, Chow and colleagues discovered that interactions between T cells and dendritic cells (DC) mediated by CXCR3 locally within tumors were required for efficacy of anti-PD1 therapy. CXCR3 deficiency potently abrogated anti-PD1 therapy. Surprisingly, CXCR3 was not important for recruiting T cells into tumors in response to anti-PD1. Instead, CXCR3 expression on tumor-infiltrating T cells was associated with greater T-cell functionality and local proliferation after anti-PD1 treatment. CXCR3 is required for T cells to find potent stimulatory CD103+ DCs within the tumor microenvironment. Thus, elimination of the CXCR3 chemokine CXCL9 specifically in CD103+ DCs also blocked the efficacy of anti-PD1 therapy. In patients receiving checkpoint blockade, the presence of CXCR3 chemokines early after treatment was predictive of responsiveness.Expert Commentary: Anti-PD1 checkpoint blockade therapy requires interactions between T cells and DCs within tumors, guided by the CXCR3 chemokine pathway. Enhancing CXCR3 chemokine production within tumors may enhance efficacy.Chow Mt, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE, et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity; Published online May 6, 2019; doi: 10.1016/j.immuni.2019.04.010.Glioblastomas (GBM) are lethal brain tumors often treated with conventional or particle radiation. Paradoxically, radiotherapy of brain tumors can potentially promote tumor recurrence or trigger secondary gliomas. Todorova and colleagues determined whether tumor suppressor lost commonly in GBM patients confer susceptibility to radiation-induced glioma. Mice with loss of one allele each of Trp53 and Pten did not develop gliomas spontaneously but did so when exposed to radiation. All tumors displayed concomitant loss of heterozygosity of Trp53 and Pten along with frequent amplification of the Met receptor tyrosine kinase, which conferred a stem cell phenotype to tumor cells.Expert Commentary: The study reveals that radiation-induced double-strand breaks cooperate with pre-existing tumor suppressor losses to generate high-grade glioma and provides a valuable mouse model that can be used to understand mechanisms underlying radiation-induced GBM development and recurrence, and to define new therapeutic strategies.Todorova PK, Fletcher-Sananikone E, Mukherjee B, Kollipara R, Vemireddy V, Xie XJ, et al. Radiation-induced DNA damage cooperates with heterozygosity of TP53 and PTEN to generate high grade gliomas. Cancer Research; Published first May 14, 2019; doi: 10.1158/0008-5472.CAN-19-0680.Patients with pancreatic ductal adenocarcinoma (PDA) have poor survival and limited treatment options. Signaling pathways required for PDA initiation are poorly understood, hindering development of therapeutic interventions. Wang and colleagues utilized Kras-driven transgenic models for PDA in the presence or absence of inflammation to demonstrate that a tripartite motif-containing protein encoded by the ataxia telangiectasia group D complementing (ATDC) gene was required for maintenance of acinar-ductal metaplasia (ADM) and progression to PanIN and PDA. Loss of ATDC prevented KRAS-induced PDA in a dose-dependent manner. ATDC was required for induction of β-catenin/SOX9 in ADM, and ectopic overexpression of β-catenin or SOX9 could restore PDA development in the setting of ATDC loss. In patient samples, aberrant ATDC/β-catenin/SOX9 overexpression was observed in ADM and maintained in PDA.Expert Commentary: This study demonstrates the requirement of the ATDC/β-catenin/SOX9 pathway for early tumor-initiating events and subsequent development of PDA. Targeting this pathway in high-risk patients may have significant therapeutic value.Wang L, Yang H, Zamperone A, Diolaiti D, Palmbos PL, Abel EV, et al. ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. Genes Dev 2019;33:641–55.Although loss of APC typically occurs in early colorectal cancer, colorectal cancer tumors remain dependent on Wnt signaling all the way through metastases, despite numerous additional mutations that enhance tumorigenesis. Using a small-molecule screen, Zhan and colleagues identified clinical MEK inhibitors as potent activators of Wnt signaling in colorectal cancer cells. Similar enhancement of Wnt activity was observed in multiple colorectal cancer cell lines and in normal intestinal cells. In colorectal cancer cells, MEK inhibition decreased the levels of Axin1, a rate-limiting component of the β-catenin destruction complex, increasing β-catenin activity. In patient-derived colorectal cancer organoids, MEK inhibition increased expression of stemness biomarkers and induced a gene signature associated with colorectal cancer relapse. This colorectal cancer reprogramming could be attenuated by treatment with Wnt signaling inhibitors. Consistent with their findings, combining MEK and Wnt inhibitors attenuated APC/KRAS-mutant colorectal cancer xenograft growth more significantly than either inhibitor alone.Expert Commentary: Clinical MEK inhibitors promote increased Wnt-dependent stemness, which may ultimately contribute to colorectal cancer relapse.Zhan T, Ambrosi G, Wandmacher AM, Rauscher B, Betge J, Rindtorff N, et al. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer. Nat Commun 2019;10:2197. doi: 10.1038/s41467-019-09898-0.Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA1-deficient triple-negative breast cancer (TNBC), however, emergence of resistance reduces efficacy. Pantelidou and colleagues demonstrate cross-talk between PARP inhibition and antitumor immune responses, whereby PARP inhibition activates recruitment of CD8+ T cells that are required for maximal therapeutic activity in BRCA1-deficient TNBC models. PARP inhibition activates the cGAS/STING pathway and subsequent production of proinflammatory cytokines more efficiently in BRCA1-deficient than BRCA1-proficient tumors. This results in activation of downstream signaling pathways in dendritic cells and CD8+ T-cell infiltration and activation.Expert Commentary: This study provides mechanistic insight into the differential activity of PARP inhibitors in BRCA1-deficient and BRCA1-proficient tumors and supports combination therapies of PARP inhibitors with immune-checkpoint blockade in BRCA1-deficient tumors.Pantelidou C, Sonzogni O, De Oliveria Taveira M, Mehta AK, Kothari A, Wang D, et al. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discov 2019;9:722–37.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.